Methods We performed a retrospective study of 24,126 PCI hospitalizations in 19,165 unique patients, between January 1, 1994, and December 31, 2009, and compared those who suffered an in-hospital PCI-CVE with the remaining control population who did not.

Results The incidence of CVE was 0.37% (n = 89), of which 22% were transient ischemic attacks. Temporal analysis showed no significant trend in incidence over 16 years (p = 0.47). Multiple clinical and angiographic predictors of PCI-CVE were identified. Multivariate logistic regression analyses revealed age, female sex, myocardial infarction within 7 days before PCI, and history of prior CVE as independent predictors of PCI-CVE, with a 19-fold increase in incidence in patients over 80 with a prior CVE history. In-hospital mortality was 19% after PCI-CVE versus 2% in controls (p < 0.001). Those who survived PCI-CVE exhibited a markedly higher risk of mortality over the subsequent 10 years (p < 0.001).

Conclusions The incidence of PCI-related CVE has remained steady over a 16-year period, despite an increase in the baseline risk profile. Age and prior history of CVE were the strongest independent demographic predictors. PCI-CVE had a markedly adverse impact on early and late outcomes.

Despite a progressive rise in the risk profile of patients undergoing percutaneous coronary intervention (PCI), and an increase in procedural complexity, temporal analyses have indicated that PCI is getting safer (1,2). Studies have revealed declines in mortality, myocardial infarction (MI), and a variety of composite nonfatal major adverse cardiac events over a 25-year period (1–3). From the patient standpoint, the most-feared component of major adverse cardiac events is stroke. Indeed, when asked to score a variety of future scenarios, elderly patients rated the possibility of major stroke as a fate worse than death (4).

A recent study from the National Cardiology Data Registry reported that the incidence of procedural stroke in all patients undergoing PCI between January 2004 and March 2007 was 0.22% (5). Limitations of this study include a lack of independent adjudication of events and variation in event reporting between sites. Moreover, strokes with symptoms lasting <72 h without residual defects are not included in this registry. Thus, it seems likely that the reported incidence is an underestimate. Two single-center retrospective studies, covering a period between January 1990 and April 2002, reported a stroke incidence of between 0.3% and 0.4% (6,7). The recent SYNTAX (Synergy Between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery) randomized trial (8), comparing coronary artery bypass grafting (CABG) with multivessel or left main PCI, indicated a stroke rate of 0.6% in patients undergoing complex PCI. Whether there has been a temporal change in the incidence of stroke as a complication of PCI remains unknown. Increases in demographic risk profile, disease burden, and procedural complexity might be expected to result in higher numbers of procedure-related stroke in the contemporary era, whereas this may be counterbalanced by the refinements in device technology and improvements in adjunctive pharmacology that have also occurred.

Factors previously found to be associated with the occurrence of PCI-related stroke include age, diabetes mellitus, renal insufficiency, impaired left ventricular function, angiographic burden of disease, and urgency of procedure (5–7). Although there are strong associations between PCI-related stroke and in-hospital and 1-year mortality (5,7), the long-term outcome of survivors of PCI-related stroke remains unknown. In this large single-center registry study, which includes the contemporary era, we report temporal trends, characteristics, predictors, and both short- and long-term outcomes of patients who suffer stroke or transient ischemic attack (TIA) as a complication of PCI.

Methods

Patient population

Patients undergoing PCI at the Mayo Clinic in Rochester, Minnesota, are prospectively followed in a registry that includes demographic, clinical, angiographic, and procedural data. Immediate and in-hospital events are recorded, and each patient is surveyed by telephone using a standardized questionnaire at 6 months and 1 year, and then annually after the procedure. Ten percent of all records are randomly audited by the supervisor for data integrity. All adverse events are confirmed by reviewing the medical records of the patients followed at our institution and by contacting the patients' physicians and reviewing the hospital records of patients followed elsewhere.

In this study, all PCIs from January 1, 1994, to December 31, 2009, at this institution were eligible for analysis. For patients with multiple PCIs within a single hospitalization, only the first PCI of that hospitalization was included. Patients who did not consent to use of their records for research were excluded, as per Minnesota state statute. There were 24,731 PCI hospitalizations of 19,657 unique patients during this period. Four hundred ninety-two patients refused authorization of their records for research and were excluded, leaving 24,126 hospitalizations for analysis. These hospitalizations were divided into 2 groups for analysis: 1) those who suffered an in-hospital cerebrovascular event (CVE) after PCI; and 2) those who did not. Medical records of all patients were reviewed to determine temporal trends, demographic and procedural characteristics, and in-hospital and long-term outcomes of CVE related to PCI.

Definitions

We defined CVE as any hemorrhagic stroke, ischemic stroke, or TIA related to PCI, based on detailed retrospective chart review from January 1994 to December 2009. Patients who underwent intervening CABG were excluded. Stroke was defined as any neurologic deficit lasting >24 h. Deficits of shorter duration were defined as TIA. All patients were evaluated by a consultant neurologist at the time of the event and diagnosis was confirmed by clinical assessment. Additionally, brain imaging (computed tomography, magnetic resonance imaging, or both) was obtained in all but 1 patient. Where there was uncertainty as to the relationship between the PCI procedure and neurologic event upon chart review, adjudication was performed by an independent consultant neurologist (A.R.).

The number of diseased coronary arteries was defined by the number of major arteries with at least 70% stenosis by visual assessment. Patients with ≥50% stenosis in the left main coronary artery were considered to have 2-vessel disease if there was right dominance and 3-vessel disease if there was left dominance. Myocardial infarction was diagnosed in the presence of 2 of the following 3 criteria: 1) typical chest pain for at least 20 min; 2) elevation of serum creatine kinase levels (or the myocardial band fraction) >2× normal; and 3) a new Q-wave on the electrocardiogram. Severe renal dysfunction was defined as a creatinine of >3.0 mg/dl or a history of dialysis or renal transplant. Cardiogenic shock was defined as a prolonged systolic arterial pressure <95 mm Hg while not on inotropes, intra-aortic balloon pump (IABP) support, or systolic arterial pressure <110 mm Hg while on inotropes or IABP support. Procedural success was defined as a reduction of residual luminal diameter stenosis to <50% without in-hospital death, Q-wave MI, or need for emergency CABG. In-hospital deaths included all deaths during the index hospital admission. Prior history of CVE was defined as a documented history of stroke or TIA that resulted in abnormalities in vision, speech, sensation, or motor function or a history of cerebrovascular (carotid) surgery.

Statistical analysis

Continuous variables are summarized as mean ± SD. Categorical variables are summarized as frequency (percentage). Because multiple hospitalizations of the same patient were included, a logistic regression model with stroke complication as the end point was used to compare risk factors between the 2 groups. Generalized estimating equations were then employed to adjust the inference for correlated observations. An autoregressive correlation matrix within individual patients was assumed such that procedures closer in time were more strongly correlated. An Armitage trend test was used to test for an increasing or decreasing trend in the incidence of stroke complications over time. Odds ratios are used to describe the magnitude of the association between stroke complications and age and prior history of stroke.

Multiple logistic regression was employed to assess associations between patient and angiographic characteristics with PCI-related CVE adjusted for other risk factors. Variables that were associated with stroke at a 0.15 significance level before adjustment were included in the model, with the following exceptions: urgency of PCI was excluded because of its subjective nature and association with pre-procedural MI; prophylactic IABP use was excluded because of its low incidence and its association with pre-procedural shock; number of segments treated was excluded because of its association with number of vessels treated. These exclusions were chosen before fitting the model. No other variable selection methods were employed. Generalized estimating equations were used to adjust for correlated observations within individuals.

Kaplan-Meier methods were used to estimate post-discharge survival in patients who underwent PCI up to December 31, 2008. Remaining patients to December 31, 2009, were not eligible for long-term analysis. Patients who died before discharge were excluded. The log-rank test was used to compare survival between patients who did and did not have a post-PCI stroke complication. Cox proportional hazards models were used to estimate the partial effect of stroke on follow-up mortality after adjusting for other risk factors. Variables that were significantly different between stroke and nonstroke patients were included as covariates in the model. Adherence to the proportional hazards assumption was assessed visually for each variable via a plot of Schoenfeld residuals over time with a scatter plot smoother. Variables that violated the assumption of proportional hazards were modeled with time-dependent variables to allow for varying effects.

Results

Incidence and type of CVE

Among 24,126 PCI hospitalizations between 1994 and 2009, the overall incidence of CVE was 0.37% (n = 89), of which 78% were strokes (deficit >24 h) and 22% TIAs (deficit <24 h). Of all CVEs, 92% were ischemic, 7% were hemorrhagic, and 1% unknown (no imaging).

Temporal trends

Temporal analysis indicated no significant trend in the yearly incidence of PCI-related CVE between 1994 and end 2009 (p = 0.47). To adjust for changes in patient demographics over time, independent predictors of PCI-related CVE identified by multivariate analysis were used to generate a risk-model for PCI-related CVE. There appeared to be a temporal reduction in the risk-adjusted incidence of PCI-related CVE over 16 years, although this trend did not achieve statistical significance (Fig. 1).

Clinical features at presentation

The most frequently occurring clinical features at presentation were limb motor weakness (49%), speech impairment (39%), visual disturbance (20%), and facial droop (18%), among a variety of symptoms and physical signs. Unresponsiveness was present in 12% (Fig. 2A). The neurovascular distribution of nonhemorrhagic events was determined by clinical evaluation and brain imaging (computed tomography or magnetic resonance imaging were obtained in 88 of 89 patients). The majority of ischemic CVEs were confined to the anterior circulation (56%), with 24% in the posterior circulation and 13% occurring in both anterior and posterior distributions (Fig. 2B). Of the 6 hemorrhagic events, 2 were in the anterior circulation, 2 in the posterior circulation, and 2 were diffuse.

(A) Symptoms and signs of neurologic event at diagnosis are charted by frequency, with motor weakness and speech impairment being the commonest clinical features at presentation. (B) Vascular distribution of ischemic strokes occurring after PCI as determined by clinical evaluation and brain computed tomography/magnetic resonance imaging. The majority were anterior-circulation events. Of note, a proportion of neurologic events involved both anterior and posterior vascular territories. Abbreviations as in Figure 1.

Procedural characteristics

Angiographic and procedural features associated with PCI-related CVE were compared with the remaining controls and are outlined in Table 2. PCI-related CVE was significantly associated with the number of diseased vessels, number of segments treated, and number of vessels treated. The urgency of PCI (elective vs. urgent vs. emergent), presence of intracoronary thrombus, and use of prophylactic IABP were also significant predictors of CVE. Notably, the use of glycoprotein IIb/IIIa agents did not influence the risk of CVE in this study. Periprocedural low molecular weight heparin usage was infrequent and did not differ between groups (6.7% PCI-CVE vs. 4.6% controls, p = 0.34). In addition, there was no statistically significant difference in the rate of ischemic stroke with radial versus femoral approaches (0.57% vs. 0.34%, p = 0.32).

Analysis by age and prior history of stroke

Further analysis according to age trends revealed that the incidence of CVE increased as patients approached or surpassed 80 years (p < 0.001) (Fig. 3A). There was a 9-fold greater risk of experiencing a PCI-related CVE after the age of 80 years compared with <50 years, with the risk increasing sharply after age 70. This age effect was markedly amplified when additional stratification was performed according to prior history of CVE (Fig. 3B). This indicated a 19-fold increase in the incidence of PCI-related CVE in patients >80 years with a preceding history of CVE, compared with those <50 years with no prior CVE history.

(A) Risk of PCI-CVE by age. Incidence of CVE increases with age (p < 0.001 for age trend), particularly after age 70 years. (B) Risk of PCI-CVE by age and prior history of stroke. Marked increase in the incidence of CVE in elderly patients with a prior history of stroke. The p values are based on odds ratios employed to describe the magnitude of the association between stroke complications and age and prior history of stroke. Abbreviations as in Figure 1.

In-hospital outcomes

Procedural success of PCI was lower in those who suffered CVE than in those who did not (70% vs. 90%, p < 0.001). Procedure-related MI, access-site complications, parameters of hemodynamic disturbance, usage of emergency IABP, requirement for emergent CABG, and post-procedural renal failure were all significantly more likely to occur in patients who suffered CVE (Table 4). Moreover, in-hospital mortality was markedly higher in the PCI-related CVE group compared with the control group (19% vs. 2%, p < 0.001). It is striking that 34% of the PCI-related CVE group suffered 1 or more of in-hospital death, MI, CABG, or repeat PCI of the original lesion compared with 7% of control patients (p < 0.001).

Long-term outcomes

Survivors were followed for a median of 7.6 years after hospitalization (interquartile range 4.0 to 11.4 years). In unadjusted Kaplan-Meier analyses, patients who suffered PCI-related CVE exhibited worse long-term survival than control patients did (both p < 0.001) (Fig. 4A). When adjustment was performed for confounding factors (incorporating all possible predictors with p < 0.15), long-term survival after PCI-related CVE remained significantly worse compared with non-CVE control patients (p < 0.01) (Fig. 4B). Somewhat surprisingly, there did not appear to be a difference in long-term survival between those who experienced a TIA versus a stroke (Fig. 4C).

Discussion

Despite progressive declines in PCI-related mortality and MI in the setting of higher-risk patient demographics (1,2), as well as an increase in rates of PCI procedural success (3), the current study indicates that the incidence of PCI-related CVE has remained steady over a 16-year period, with an overall incidence of 0.37%. Other important findings include the very strong association of age and previous CVE history with risk of experiencing a PCI-related CVE, high rates of in-hospital mortality, and markedly adverse long-term outcomes in those who survive.

Demographic features associated with PCI-related CVE in this and other studies (6,7) are also associated with atherosclerotic disease burden. This likely underlies the cause of PCI-related CVE in many cases. For example, the presence of aortic plaque, particularly if mobile, is associated with risk of catheter-induced embolization (9), and atherosclerotic debris derived from the aorta is a frequent finding in catheter aspirates (10,11). Procedural complexity was also associated with risk of CVE. Potential mechanisms underlying this association might include a greater propensity for thrombus formation on devices, displacement of intracoronary thrombus, air embolization, and a higher likelihood of periprocedural hypotension resulting in cerebral hypoperfusion. Given the increase in numbers and proportion of PCI procedures being performed in higher-risk populations (1,2), it is perhaps reassuring that the rate of PCI-related CVE has not increased in parallel. One can speculate that improvements in device technology and pharmacological therapy have tempered this potential rise. In this regard, progressive reductions in the profile of balloons and stents over time have enabled the use of smaller-diameter guiding catheters for device delivery. Compared with their larger-diameter counterparts, smaller-caliber guides might be less likely to disrupt atheroma from the aortic wall (10). Improvements in antiplatelet pharmacotherapy, with increased use, and the widespread implementation of statin therapy over the past 15 years might also be expected to favor a reduction in procedural CVE via plaque stabilization and antithrombotic mechanisms.

Although the incidence of PCI-related CVE is comparable to historic single-center studies (6,7), the proportion of hemorrhagic strokes in the current study is considerably lower. A study from the National Cardiology Data Registry comprising a more contemporary population did not distinguish between ischemic and hemorrhagic strokes (5), and as such, it remains unclear whether the lower hemorrhagic rates in our study reflect a reduction over time or a variation in practice patterns, such as the infrequent administration of fibrinolytic therapy and low molecular weight heparins in our patient population.

The data suggest that outcomes after PCI-related CVE are poor. In line with historic studies (6,7), in-hospital complications were markedly more frequent than for control patients and included procedural failure, MI, severe hemodynamic disturbance, emergency CABG, and access-site complications. Given this, the high rate of in-hospital mortality (19.1%) may be less surprising. Of note, nearly all in-hospital deaths occurred in patients who suffered a significant neurologic deficit, with only 1 death occurring in a patient who had a procedural TIA. The TIA patient experienced no other complications, but developed unheralded pulseless electrical activity 2 days after PCI for an acute coronary syndrome.

Survivors of PCI-related CVE also appeared to experience a long-term mortality disadvantage. This disadvantage persisted even after adjustment for confounding factors. Although this could be attributed to presence of unmeasured confounders, another explanation might be the higher risk of developing life-threatening noncardiac morbidities (e.g., pneumonia, deep vein thrombosis) that occur after in CVE survivors.

In the current study, the 2 most powerful independent predictors of CVE were age and prior history of CVE, with the rate of procedural CVE approaching 2% in patients over 80 years with a prior history of stroke. This perhaps underscores the importance of considering demographic characteristics when assessing procedural risk and obtaining informed consent. Although many of the risks for the development of PCI-related CVE are not modifiable, it would appear prudent to ensure optimal pharmacological therapy, minimize guiding catheter diameters, and take measures to avoid procedural hypotension particularly in higher-risk patient subgroups such as these. Again, although it remains to be determined whether newer device technologies designed to deflect or capture displaced embolic material will prove effective, future studies targeted toward high-risk populations such as those identified here would seem reasonable. Given the volume of diagnostic and interventional cardiac catheterization procedures performed, it is likely that thousands of CVE complications occur annually in the U.S. alone (12). Moreover, projected increases in the use of structural interventions such as transcutaneous aortic valve replacement might further increase rates of CVE related to cardiac catheter-based procedures. The current study, indicating adverse short- and long-term outcomes after such complications, underscores the importance of developing risk scores to identify groups at higher risk in advance to facilitate timely implementation of treatment measures such as early fibrinolysis (12) or acute neuro-endovascular intervention when appropriate (13).

Study limitations

The present study is a retrospective analysis from a single institution, which might limit its broad application. Concurrent pharmacological therapy, measures of risk-factor control, and presence of atrial fibrillation could have influenced CVE risk and were not available for the study population. National Institutes of Health Stroke Scale assessment was not available for a significant number of patients, such that stratification of outcome by degree of impairment was not possible. Although records were scrutinized to ensure that all events included were appropriate, it is possible that several CVEs went unrecognized (nonspecific symptoms, brief duration, occurrence of sudden death without post-mortem evaluation), thereby underestimating the true incidence. Moreover, as has recently been described with transcatheter aortic valve implantation (14), it is highly likely that clinically silent cerebral embolic events also occur with PCI, and these would not have been recorded in our study.

Footnotes

Dr. Gersh received research funding from Ortho-McNeil Janssen, Amorcyte Inc., Merck Sharpe & Dohme, Abbott Laboratories, GE Healthcare, St. Jude Medical, Medispec, Merck & Co., and Boston Scientific. All other authors have reported that they have no relationships to disclose. Mark Hlatky, MD, served as a Guest Editor for this paper.